Abstract There are currently no drugs or other therapeutic interventions that can reverse or halt the progression of Alzheimer's disease (AD). Age is by far the greatest risk factor for AD, and it is known from studies in both mice and humans that neuroinflammation is increased with old age and to an even greater extent in AD. Therefore, a drug that could reduce neuroinflammation and at the same time be neuroprotective would have an excellent chance in the clinic. To address this problem, we devised a drug discovery program based upon a unique set of phenotypic screens to identify small molecules which reduce the toxicities to cortical neurons that occur with old age and which also have anti-inflammatory activity. Our initial studies using this approach led to the identification of the flavonoid fisetin as a molecule that modulates neuroinflammation in ways that are beneficial for altering AD progression. A series of much more potent fisetin derivatives was then synthesized by SAR-driven iterative chemistry. Many of these derivatives maintain in vitro anti-inflammatory activity. Importantly, the derivatives do not suffer from the intellectual property challenges of the natural product fisetin and are covered under several pending patents held by the Salk Institute. From the 160 derivatives synthesized, we selected the best seven derivatives that maintain the biological activities of fisetin, including its anti-inflammatory activity, for further studies. Based on these studies, we identified CMS121 as a modulator of neuroinflammation and a clinical candidate for the treatment of AD. Importantly, we have shown that CMS121 prevents most of the behavioral and physiological changes associated with aging and the sporadic AD phenotype in both a transgenic AD mouse and in a novel mouse model of old age-associated sporadic AD that accounts for 99% of human AD cases. Moreover, preliminary toxicology studies demonstrate that CMS121 has undetectable genotoxicity. The overall goal of the research described in this application is to complete the studies needed for an IND submission to the FDA. To do so we wish to utilize the phase IIB program which is designed to address the funding gap between a phase II SBIR/STTR award and the external financing needed to advance a product to commercialization. Consistent with the purpose of the Phase IIB program which was added in recognition of the fact that most small businesses cannot afford the equipment nor the full-time expertise required for expensive IND-enabling studies, much of the work in the proposed research plan will be conducted by CROs. We will provide overall supervision and direction as well as coordination of the different steps that need to be completed in order to file an IND submission. Together, these studies should place CMS121 in an excellent position to obtain outside funding and begin phase I clinical trials.